DR. BARKER: Well, as you know, cancer will take the lives of 1,500 people today; 560,000 people will die from this disease this year; and nearly 1.5 million people will receive a diagnosis of cancer this year. That’s really – those statistics are really daunting, but if you look forward into the future, and not that far into the future, 12, 15 years even, we could see an increase of cancer approaching 50 percent in some estimates, certainly in the 30 percent range, and from 30 to 50 percent means an enormous number of increase in cancer cases.

SUSAN DENTZER: Overall that means how many Americans?

DR. BARKER: If you look at the number of cancers that are being diagnosed today in terms of new cancer cases, if you do the numbers actually, you could – you could nearly see a doubling of the number of diagnoses in new cancer cases in a reasonably short period of time – 12 to 15 years.

SUSAN DENTZER: So we’re essentially now looking at one out of three Americans having a cancer diagnosis. You’re saying it could go as high as one out of two?

DR. BARKER: Well, I think the one out of three number will probably hold, but it’s that the number of cases per se is going to go up. In other words, the number of cases and number of Americans that get diagnosed with the disease.

So today about one out of three Americans can expect to get cancer. And if you look at the aging of the population, the number of cancer cases will increase significantly.

SUSAN DENTZER: Just recently the American Cancer Society put out new numbers, suggesting that mortality was continuing to decrease, particularly in certain cancers. How do we put that story together with the story you’re telling us about?

DR. BARKER: Very exciting, that story, and that is a real decrease, and we believe it will continue to decrease. I think it’s a combination of several things – earlier detection of the disease, certainly, and some of the biomarkers that we’ll talk about that are being used very effectively. And I think better treatment – if you get earlier diagnosis, you get better treatment and you get better survival. So, you know, I think all these things are beginning to really add up, but ultimately this is all deriving from the science we’ve been doing over the last nearly 34, 35 years, and it’s now starting to really pay off for – for the cancer patient.

What is a biomarker?

SUSAN DENTZER: Let's put the biomarker story in context, then, with this enormous surge in the number of cases we're going to be experiencing. How important is the quest for biomarkers and biomarker discovery in the context of battling this future of a very major increase in numbers of cases of cancer?

DR. BARKER: Well, if you look at this increase that we're looking at and expecting in terms of the aging of the population and cancer, we have to have better ways to detect this disease earlier. We have to treat it in a much more charted fashion. We have to be able to know when cancer is going to come back or recur, and biomarkers are actually probably the single biggest hope we have to accomplish those goals.

SUSAN DENTZER: Now let's talk about the continuum of efforts that NCI is engaged in.

DR. BARKER: So if you - let's step back and ask ourselves what is a biomarker. Let's start there. And biomarkers are variously defined. It's a complex term that captures an enormous amount of science. But really it's measuring the change in a normal cellular process, or a malignant or cancer cell process. It can also - it's also used sometimes to measure changes following treatment - changes in biomarkers.

So that means that biomarkers can be changes in genes, changes in proteins, some combination thereof. It can even be imaging, for example. Images can qualify as biomarkers if it's measuring changes in a specific organ or a specific process.

So these biomarkers actually, if you start all the way back at prevention and you move through prevention, early detection, treatment, follow-up care, etc., biomarkers can then form every step of that process. However, the biomarker story is one that will require that we also go back in another continuum - that's the research continuum - with discovery.

So we have to discover biomarkers, we have to validate biomarkers, and then we have to use biomarkers in clinical trials, and then we have to actually make products that patients receive that are actually biomarker based.

So what NCI has tried to do over the last several years, and this is the culmination of many years of work, is to first of all go back to discovery, and we're doing several projects in discovery. All of our individual investigator grants are really based in discovery, but we're doing two additional projects that are really pretty exciting. One is called the Cancer Genome Atlas, and it's a pilot project. It's a very big undertaking, but we've teamed up with the National Human Genome Research Institute to try to discover all the genetic changes in cancer.

We're starting with three cancers and that's gliomas, or brain tumors, ovarian cancer, and lung cancer. That's a very big project, so doing a pilot project to see if it's scalable - can we do this for all cancer - is a three year project, and we're spending about $100 million between the National Human Genome Research Institute and ourselves on that project.

NCI initiatives

SUSAN DENTZER: Just to stop you there, since cancer is a disease where the gene changes don't just happen once, they're happening continually throughout the disease process, that's an incredible undertaking.

DR. BARKER: The Cancer Genome Atlas, or TCGA as we've come to call it, is a very, very big undertaking because as you point out, cancer is the disease of genes, but it's a disease of accumulation of genetic changes, and so there will be lots and lots of genetic changes.

So our challenges here are quite daunting, is one to find all those genetic changes, but to also separate the signal, which is really important in terms of those genetic changes, from the noise, because there are a lot of genetic changes that won't have much to do with cancer.

So we have - we have actually, we believe, an absolutely superb team to work this out, and all the way from some of the best of our cancer biologists, to the genemicist, to the bio-informaticist who is going to work on this and put all this data together using specimens actually from clinical trials.

So if there's a chance to do this well, and I think there is, and we believe there is, the timing is right, this is probably - will be one of the most important projects we've undertaken in medicine today.

SUSAN DENTZER: So continuing on the continuum --

DR. BARKER: So going back to the way genes actually work - so when mutations occur or changes occur in genes, those get translated into sort of the workhorses of the cells, which are proteins, and proteins are going to be there in much larger numbers in terms of changes than genes. So we have undertaken another program at the NCI called the Clinical Proteomics Technology Initiative. We're trying to bring some standardization to the discovery of proteins so they can be used as biomarkers.

So the things we're working on actually are begin to standardize the technologies, things like mass spectrometry, which are used to measure changes in proteins, just to create the reagents here, so that we have common sets of reagents that all scientists can use.

SUSAN DENTZER: Let's define reagents and why we need them.

DR. BARKER: So reagents actually will be antibodies, or parts of antibodies, because most of the proteins that we have used to date actually have to be developed by isolating them, finding them, and testing for them using antibodies. And antibodies are your body's response to an antigen or a foreign protein, or a self-protein. And so we are going to be able to create sets of reagents or sets of antibodies, or parts of antibodies that the entire community can access, and then protocols for how to do this, you know, and how to get reproducible results.

And so our clinical Proteomics technology initiative is underway. Again, it's - it's a much earlier project in some ways than the Cancer Genome Atlas in the sense that we'll be developing a lot of the technologies and standardizing them, and if you start looking at the size of the Proteomics problem, it's much, much bigger. We believe there could be anywhere from 100,000 to a million different proteins that might be important in cancer, and if you look to date in the literature - published literature from scientists, there's probably a little - there's probably a little over 1,200 proteins that have been discovered and seem to be linked to cancer.

To date we've only approved - FDA's approved about 12 for use in the clinic, so you can see there's quite a disconnect. And if there - let's say there's anywhere between 100,000 and a million proteins, there are many, many m ore proteins to discover, obviously. But we need the standardized technologies, and we need the standardized reagents, and we need the protocols and the laboratories to be able to reproduce each other's results.

So that's the project that we've undertaken, and if you move now across the continuum into development, we have several programs at the NCI where we're developing biomarkers. The first of those is called the early detection research network, and there our goal is to validate biomarkers in the clinic, and in patients actually. And I should tell you it is a very rigorous process. It's very hard to qualify your biomarker for the early detection research network. You have to go through a lot of hurdles because it's a very expensive process to put this biomarker into the clinic.

From lab to clinical practice

SUSAN DENTZER: And let's just say what we mean by validation. What are we getting at?

DR. BARKER: Validation means that you would develop a clinical trial, and you would basically predict that your biomarker would have a certain effect. Let's say that you were measuring the change in some cellular process, and you were treating a patient and you - you told the regulators, the FDA in this case, that if I treat this patient with this particular drug, there will be a definitive and reproducible change in a cellular process that I can measure. So you have to measure -

SUSAN DENTZER: To measure what protein will go up or it will go down.

DR. BARKER: It will go down, that's exactly right. And you can measure it reproducibly. And you have to show in patient after patient after patient that you can measure that reproducibly because patients are very heterogeneous. They are quite different. So your expression of that protein and my expression of that protein, even though we have the same disease, we're being treated by the same agent, might be different.

So validation requires what we call randomized trials, which means that you have large numbers, and you have to have statistical validity in these trials. You have to do enough patients to be able to find all those differences. So that's the - that's the early detection research network.

Now, if you continue to move across this continuum, we have something called the integrated cancer biology program, or systems biology as it's come to be known, where we're looking at how all these pathways and the cells come together in malignant cells, and that will tell us a little bit more about which biomarkers might be critical, and have a bigger impact on the cell, for example, than some of the - some of the smaller regions that we're looking at.

Now, if you move further into that continuum, so now we're in development - so let's move over to how are we going to deliver these protein biomarkers of genome biomarkers or whatever, we have a program in nanotechnology. It is becoming obvious to us that we are going to have to measure lots of things in cells. And so nanotechnology, as you know, is a science that measures at a very, very small level, much, much smaller than water molecules, for example, or at the size of water molecules, 10 angstroms, you know, very, very small. And so we've developed a program to be able to put lots and lots of these biomarkers onto platforms so that we can measure them in patients - measure large numbers of them in patients in the future.

And we then have on the very end of this continuum then, we have a very robust clinical trials infrastructure that will be able to test these biomarkers and clinical trials. And then after - after we can establish the validity of a clinical trial as judged by the FDA for a biomarker, then the private sector can actually make it and send it to patients. And that's a very long continuum.

We hope for biomarkers that won't be as long as drug development, which now takes roughly 10 years, and can cost up to a billion dollars. We think that biomarkers will enable that process. Number one, it will probably reduce the time it requires to develop drugs as well as reduce the cost of developing drugs.

SUSAN DENTZER: And on the clinical trial piece of it, we're on the eve of launching a trial, as we were discussing a moment ago. Let's discuss that anew. Tell me about this trial that is about to get underway.

DR. BARKER: So one of the major gaps we have here in terms of biomarker validation is, in fact, the relationship with the FDA that's required in terms of the science that needs to be established before FDA can really judge what a biomarker is, and whether or not it's effective.

So NCI has been working with FDA over the last nearly five years now to establish some guidance for how we would set up trials for biomarkers. And through something called the Interagency Oncology Task Force, we have developed something called the Oncology Biomarker Qualification Initiative. We have lots of acronyms in the government, as you well know, and through that we have designed two trials actually to measure the impact of biomarkers, working with FDA and also with the Center for Medicare/Medicaid Services.

Through the Interagency Oncology Task Force, we have actually developed something called the Oncology Biomarker Qualification Initiative, which is actually a collaboration between the FDA, the NCI, and CMS, and we are hoping to qualify biomarkers, and the first two trials that we have actually designed, the first one is in non-Hodgkin's lymphoma, and the second one is in lung cancer. Both of them actually are going to get underway probably here in the next two months.

The biomarker that we're looking at is actually something called FDG PET. It's a functional imaging biomarker. It's based on actually changes in the metabolism of cancer cells versus normal cells, and it's actually measuring changes in the way glucose is metabolized in these cells. And we have a long history in non-Hodgkin's lymphoma of using this biomarker, and we believe that this is one of those that will be reasonably straightforward to qualify with FDA, and we are using the same approach for lung cancer. The two diseases are different, but this - this functional imaging should work in both of these trials.

Treating non-Hodgkin's lymphoma

SUSAN DENTZER: So literally, is this going to be for diagnosing non-Hodgkin's lymphoma, or for measuring changes in cells based on treatment of the disease?

DR. BARKER: This is going to be actually to look at the latter, to look at how are the cells changing with treatment, and is the treatment actually working. And you can imagine, and going back to our definition of biomarkers, which is really sort of a change that you can measure, whether it's in a normal cell or a neoplastic cell, you can imagine that biomarkers are going to be used for all kinds of things in the future. They're going to be used to detect diseases early, they're going to be used to actually hopefully even detect diseases early enough to prevent the disease. They're going to be used to inform drug discovery, so you can actually develop targeted therapies to these biomarkers.

They're going to be used actually to choose the right therapy for patients, so you'll go in a - you'll be placed in a clinical trial based on your expression of a biomarker. It will be used to monitor how you're doing in the clinical trial, and they'll also be used as prognostic factors, or predictive factors to say that you're doing well, you could do well, and also to tell you when your cancer recurs.

So you can see why we're so excited about biomarkers because if you could do any of those things well right now in terms of predicting who is going to respond, for example, you could improve - you could improve almost exponentially the way that patients actually respond to treatment for example.

So we're very excited about every phase of biomarker use, and that's why the NCI is actually investing lots of resources and funding lots of investigators to actually work on this problem.

SUSAN DENTZER: I'd like to just make it very concrete for people that in this trial involving non-Hodgkin's lymphoma, essentially what people will be doing is treating patients for the disease, and then looking with a PET scan at these changes that you can actually see in cells.

DR. BARKER: As these patients with non-Hodgkin's lymphoma are treated, both before they're treated and after they're treated, the clinician will look at the PET scan, this functional imaging scan, and be able to determine if the disease is getting better or not, and - or getting worse in some situations. So they'll be able to maybe treat earlier, where they would have waited, and they may actually not - hopefully not overtreat. Sometimes we're also overtreating patients.

So this is a - this will be a good test of whether or not FDG PET functional imaging is going to qualify as a biomarker with FDA, and also if it's going to really help patients.

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